Tumor immunology Flashcards
- State the concept of the immunosurveillance hypothesis. Discuss how data from immune suppressed and immunodeficient patients support this hypothesis.
Tumor Immunosurveillance:
The immune system destroys developing tumors by recognizing foreign antigens that are generated during the transformation process.
- Tumors increase with immune suppression.
- A small but significant number of tumors spontaneously regress.
- Tumor infiltrating lymphocytes (TILs) are detected in tumors and correlate with improved prognosis.
- Describe the concept of immunoediting
- Describe the origin and relative immunogenicity of the following kinds of tumor antigens: viral, mutant/neoantigens, oncofetal, and differentiation.
Neoantigens:
What are they?
Do all the mutation of tumors code for neoantigens? Why?
Can be presented by MHC molecules to T cells.
Recent amazing progress in analyzing a tumor’s genome and exome have helped us understand the antigenic nature of human tumors. Some mutations can be expressed and presented by MHC molecules to T cells.
-Human melanoma, for example, has many mutations; e.g., one person’s tumor harbored 3,000 protein-altering mutations. It is among the mutations that CTL find **mutated protein antigens—neoantigens—to control tumors. It is now clear that the more mutations, the more neoantigens, and the more CTL—thus, more targets for immunotherapies.
Although tumors have many mutations, not all will code for neoantigens. Some will be in stretches of protein not easily cut to make peptides of the right length for MHC presentation. Some will not code for “anchor” amino acids with side-groups that interact strongly enough with MHC so that they “stick” in the groove. Many will not present the changed amino acid in a position that interacts with a T cell receptor. In a technical tour-de-force, a tumor with 4,285 exomic coding variations was predicted to have 170 neo-epitopes (that could bind to MHC); of these, 7 were predicted to actually be immunogenic. And only three could be validated as recognized by CTL3.
- Describe the origin and relative immunogenicity of the following kinds of tumor antigens: viral, mutant/neoantigens, oncofetal, and differentiation.
Viral
HTLV-1 and 2 are agent for what cancer?
Microbial gene products:
In humans about 20% of tumors are caused directly or indirectly by viruses. They include HTLV-1 and -2, which are agents of leukemia/lymphoma.
- Cervical cancer is caused by human papilloma virus. Liver cancer is the consequence of a hepatitis virus infection.
- Epstein Barr Virus can induce Burkitt lymphoma and nasopharyngeal carcinoma.
- The presence of the bacterium Helicobacter pylori is associated with gastric carcinomas. These antigens are typically foreign to the immune system.
- Describe the origin and relative immunogenicity of the following kinds of tumor antigens: viral, mutant/neoantigens, oncofetal, and differentiation.
Oncofetal antigens
When should you use a kit to test for CEA? Why?
Oncofetal antigens are made in normal fetal tissues, not in normal adult tissues, and re-expressed in tumors.
The most familiar is carcinoembryonic antigen (CEA), found in the blood of patients with colon carcinoma and other cancers. There are commercially available kits to detect CEA in blood. They should not be used as a routine screening test. Why not? Too many false positives. The proper use of CEA measurement comes when you have a high index of suspicion of colon cancer; or, when such a cancer has been removed, to confirm complete excision (levels fall to 0 and remain there) or to give early warning of recurrence. Are these antigens recognized as foreign? Self?
- Describe the origin and relative immunogenicity of the following kinds of tumor antigens: viral, mutant/neoantigens, oncofetal, and differentiation.
Differentiation antigens
These lineage-specific antigens can be greatly overexpressed in tumors.
The best studied are those from malignant melanoma usually over expressed proteins required for pigment generation. (Ever wonder why melanomas are dark in color?) 30% of breast and ovarian cancers overexpress the human EGFR-2 gene product (HER-2/neu). T cell responses to HER-2/neu can be induced. (What does this say about selection of HER2/neu-specific T cells in the thymus?) Prostate-specific antigen (PSA) appears in the blood of many men with prostate cancer, and its detection has been used in screening programs, though its utility as a guide for treatment has come into question.
- Define carcinoembryonic antigen (CEA) and discuss its usefulness in screening for, diagnosis, and follow-up of colon cancer.
What type of antigen it is?
Oncofetal antigens are made in normal fetal tissues, not in normal adult tissues, and re- expressed in tumors. The most familiar is carcinoembryonic antigen (CEA), found in the blood of patients with colon carcinoma and other cancers. There are commercially available kits to detect CEA in blood. They should not be used as a routine screening test. Why not? Too many false positives. The proper use of CEA measurement comes when you have a high index of suspicion of colon cancer; or, when such a cancer has been removed, to confirm complete excision (levels fall to 0 and remain there) or to give early warning of recurrence. Are these antigens recognized as foreign? Self?
- Define what is meant by checkpoint inhibitory therapy for tumors, and describe their mechanisms of action.
CD28 expressed by T cells bind ____ on the APC, which results in coestimulation.
To decrease immune response what do T cell downregulate and upregulate on its surface?
CTLA-4 signal is ______.
What another inhibitory checkpoint do T cells upregulate late to decrease immune response?
How is this used by tumors?
►Inhibitory checkpoint blockade.
When a T cell first engages an APC, it upregulates CD28, which engages CD80 and CD86 on the APC. This results in co-stimulation of the T cell (“co-” meaning, along with TCR engagement of peptide-MHC.)
After several days, when the immune response should begin to wind down, CD28 is downregulated and CTLA-4 appears on the T cell surface. It has higher affinity for CD80/86, and its signal is inhibitory; the CTL is, effectively, turned off. Similarly, late in T cell activation, the CTL upregulates another inhibitory checkpoint, PD-1, which is engaged by PD-L1 on the APC. All this is normal, to keep immune responses in check.
►But most tumors learn quickly to express CTLA-4 and PD-1 ligands; these turn off the invading T cells (which are often observed standing helplessly on the outskirts of a tumor.) Perhaps not surprisingly, in many cases the CD80/86 and PD-L1 are not actually on the tumor, but on lymphocytes and phagocytes that are in the tumor and probably responding to tumor- derived signals to express these ligands. In any event, the result is that there are CTL near or in the tumor that could do the job, but their off-buttons have been pushed. ,.
- Define what is meant by checkpoint inhibitory therapy for tumors, and describe their mechanisms of action.
What are some issues with ipilumab?
Check point inhibitors
Checkpoint inhibitors
- Define chimeric antigen receptor T cell (CAR-T) therapy, and explain why it is called “chimeric” and why we have had better success with leukemias and lymphomas than solid tumors with this therapy.
- Define chimeric antigen receptor T cell (CAR-T) therapy, and explain why it is called “chimeric” and why we have had better success with leukemias and lymphomas than solid tumors with this therapy.
- Describe a mechanism by which BCG treatment causes tumor regression.
Innocent bystander killing.
BCG (the tuberculosis vaccine) instilled directly into the bladder on multiple occasions is the treatment of choice for superficial bladder carcinoma. It’s likely that lots of angry M1 macrophages, attracted by activated Th1 cells, non-specifically kill the easily- reached tumor cells.
